Saturday, 25 October 2014

How does Gilenya work and avoid PML risks?

Mehling M, Brinkmann V, Antel J, Bar-Or A, Goebels N, Vedrine C, Kristofic C, Kuhle J, Lindberg RL, Kappos L.FTY720 therapy exerts differential effects on T cell subsets in multiple sclerosis. Neurology. 2008 Oct 14;71(16):1261-7.

BACKGROUND:  The oral immunomodulator FTY720 has shown efficacy in patients with relapsing multiple sclerosis (MS). FTY720 functionally antagonizes sphingosine 1-phosphate receptor-1 (S1P1) on T cells and consequently inhibits S1P/S1P1-dependent lymphocyte egress from secondary lymphoid organs. Little is known about the phenotype and function of T cells remaining in peripheral blood during long-term FTY720 treatment.
METHODS:T cells from FTY720-treated, interferon-beta (IFNbeta)-treated and untreated patients with MS, and healthy donors (HD) were analyzed with respect to T cell subpopulation composition, proliferation, and cytokine production.
RESULTS:In FTY720-treated patients (n = 16), peripheral blood CD4+ and CD8+ T cell counts were reduced by approximately 80% and 60% when compared to the other groups (IFN beta: n = 7; untreated: n = 5; HD: n = 10). This related to selective reduction of naive (CCR7+CD45RA+) and central memory (CCR7+CD45RA-) T cells (TCM), and resulted in a relative increase of peripheral effector memory (CCR7-CD45RA- [TEM] and CCR7-CD45RA+ [TEMRA]) T cells. The remaining blood T cell populations displayed a reduced potential to secrete IL-2 and to proliferate in vitro, but rapidly produced interferon-gamma upon reactivation, confirming a functional TEM/TEMRA phenotype. Neither FTY720 nor FTY720-P directly suppressed proliferation or cytokine production by T cells.
CONCLUSION:Therapeutic dosing of FTY720 reduces naïve T cells and TCM, but not TEM, in blood, without affecting T cell function. This is presumably because naive T cells and TCM express the homing receptor CCR7, allowing recirculation to secondary lymphoid tissues on a regular basis and, thus, trapping of the cells by FTY720 in lymph nodes.

Johnson TA, Lapierre Y, Bar-Or A, Antel JP. Distinct properties of circulating CD8+ T cells in FTY720-treated patients with multiple sclerosis. Arch Neurol. 2010; 67(12):1449-55. doi: 10.1001/archneurol.2010.312 
OBJECTIVE:To define the capacity of peripheral blood CD8(+) T cells from patients with multiple sclerosis (MS) receiving Gilenya/fingolimod (FTY720) to migrate in response to chemokines that contribute to trafficking into the central nervous system.
DESIGN:Peripheral blood T cells of FTY720-treated patients with MS (MS-FTY) are mainly CD8(+) CCR7⁻ effector memory cells as CCR7(+) T cells are inhibited from exiting from secondary lymph nodes. Migration of CD8(+) T cells from MS-FTY patients and untreated donors to chemokines CXCL12 and CCL2 was assayed in vitro. Expression of CCL2 receptor (CCR2), CCR7, CD28, and CD27 on CD8(+) T cells was determined by flow cytometry.
RESULTS:In vitro addition of active (phosphorylated) FTY720 increased migration of CD8(+) T cells from untreated patients to CXCL12 and CCL2. The CD8(+) or CD8(+) CCR7⁻ T cells from MS-FTY patients migrated less to CXCL12 and CCL2 compared with those from untreated donors. The proportion of CD8(+) CCR7⁻ cells that express the CCL2 chemokine receptor, CCR2, was significantly reduced in the MS-FTY group. The CD8(+) CCR7⁻ cells from the MS-FTY patients were enriched with CD27⁻ CD28⁻ (late effector) memory cells, a population with reduced expression of CCR2 compared with early (CD27(+) CD28(+)) effector memory cells.
CONCLUSIONS:Therapy with FTY720 results in a subset of CD8(+) T cells with distinct functional migratory properties dominating the peripheral circulation. The expected forthcoming use of FTY720 as a sustained therapy for MS will clarify how this redistribution of lymphocyte populations affects the overall process of immune surveillance.
Mehling M, Lindberg R, Raulf F, Kuhle J, Hess C, Kappos L, Brinkmann V.Th17 central memory T cells are reduced by FTY720 in patients with multiple sclerosis. Neurology. 2010 Aug 3;75(5):403-10. doi: 10.1212/WNL.0b013e3181ebdd64.
OBJECTIVE: FTY720 is a sphingosine 1-phosphate (S1P) receptor modulator that showed efficacy in phase II and III clinical trials in patients with multiple sclerosis (MS). FTY720 inhibits lymphocyte egress from secondary lymphoid organs into the peripheral circulation, thereby reducing the number of circulating naïve and central memory T cells, but not effector memory T cells in blood. Little is known to which of these memory T-cell subsets interleukin 17 (IL-17)-producing T cells (Th17 cells) belong, which are considered to be key mediators of inflammation in MS, and how they are affected by treatment with FTY720. In this study, we determined the phenotype and frequency of Th17 cells in blood of untreated, FTY720-treated, and interferon-beta (IFNbeta)-treated patients with MS and healthy donors.
METHODS:In a prospective observational study, circulating T cells were phenotypically characterized and Th17 cells enumerated in T-cell subsets ex vivo. Production of IL-17 upon activation and expression of the Th17-specific transcription factor RORC2 was assessed in vitro.
RESULTS:Th17 cells were found primarily within central memory T cells in all study populations. FTY720 treatment reduced blood central memory T cells, including RORC2+ and IL-17-producing T cells, by >90%. FTY720 did not per se affect IL-17 production when added to activated T cells in vitro.
CONCLUSION:Phenotypic Th17 cells are defined by a central memory T-cell phenotype. FTY720 reduces these Th17 cells in blood. This is presumably because central memory T cells are retained by FTY720 in secondary lymphoid organs.
PML has been rearing its head again. It is the nemesis of Tysabri but as about 50% to 60% of MSers are infected with the virus that causes PML and it has to be a risk factor for anybody who is immunosuppressed. 
Tysabri stops white bloodcells gettinginto the brain and so it cannot eliminate JC virus that maygetinto brain cells. If you don't have white blood cells in the blood it is also going to be a risk. 
So why hasn't their being loads of PML in people taking interferon beta and copaxone? I suspect they are not very immunosuppressive.
 So what about Alemtuzumab and Gilenya? Will they cause PML?
Quite possibly it is a numbers game. As more people use the drug for longer then the chances of this rare event increases. 
However, PML appears to occur with long term immunosuppression and leucopaenia (Loss of white lood cells from the blood). 
Whilst Alemtuzumab causes such long-term immunosuppression of the T cell response, it has to be said that Alemtuzumab will be out of the system within a month or so. After that people are drug free and therefore anti-viral cells can expand and do their job of getting rid of virus. 
However with Gilenya you take it every day and it effectively empties the blood of white blood cells because they get stuck in the lymph glands and so shouldn't this have the risk seen with Tysabri?
There has been enough time for PML to have reared its head. It has of course but most of these have been following tysabri treatment.
However, it has to repeated that it is thought that Gilenya is not a blanket inhibitor of T cell function. It blocks naive (T cells that have not yet been stimulated by their target) and central memory cells (which is suggested to contain the population of cells that cause MS. It also hits a subset of memory B cells too) but not the Effector T cell population. It is this population that it has been suggested to contain viral immunity and so may give some protection  against the JC virus. However of course this is not absolute as there have been problems of viral infections such as Herpes in people taking Gilenya but this bit of biology may contribute to the pausity so far of PML in people taking Gilenya.
CoI: None   ProfG: multiple


  1. I hope you are right about the lower risk of PML on Gilenya. But the story is very short - is it 4 years since FDA approval? And who is taking Gilenya... usually people who have been taking other drugs previously, usually Tysabri.. if it so happens that they get PML, then Tysabri is to blame.
    ( I am on Gilenya and with low white and lymphocyte count - if I shut up suddenly then you know what hit me :-). Oh no, I have been on DMF previously... let's blame it on DMF ;-)

  2. First ,I would like to thank you all for this great blog , I don't comment much but I'm a regular follower :)

    I wonder what are the implications of trapping the above mentioned subset of T-Cells in secondary lymph nodes ; does the body try to compensate by producing more lymphocytes ? What happens eventually to "trapped" lymphocytes ?, and at some point don't the secondary lymph nodes have a "capacity" ?

    I was able to get on Gilenya at CIS even though I don't fulfill MacDonald criteria as my MRI features are very consistent with MS : a significant lesion burden(above 15 , mostly brain 2 in c-spine) ,ON attack & right foot numbness ,and a positive LP OCB. Sometimes I feel I am medicating my self ,but I do believe in early aggressive treatment.


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